A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury

Rolf Dario Frank; Todd Holscher; Gernot Schabbauer; Michael Tencati; Rafal Pawlinski; Jeffrey I. Weitz; Nigel Mackman

doi:10.1160/TH06-07-0418

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(06): 802-806
DOI: 10.1160/TH06-07-0418

Wound Healing and Inflammation/Infection

Schattauer GmbH

A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury

Rolf Dario Frank

¹Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

²Department of Nephrology, University Hospital RWTH Aachen, Aachen, Germany

,

Todd Holscher

¹Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

,

Gernot Schabbauer

¹Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

,

Michael Tencati

¹Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

,

Rafal Pawlinski

¹Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

,

Jeffrey I. Weitz

³Departments of Medicine and Biochemistry, McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada

,

Nigel Mackman

¹Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

› Author Affiliations

Abstract

Summary

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in an antithrombin-dependent fashion.This newly developed anticoagulant is used in the prevention and treatment of venous thromboembolism. Recently, we showed that fondaparinux reduces inflammation and protects the kidney from ischemia-reperfusion (I/R) injury. However, the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection is unknown.To address this, we chemically modified fondaparinux to abolish its affinity for antithrombin and analyzed the effect of this non-anti- coagulant (NAC)-pentasaccharide on binding of U937 cells to P-selectin in vitro and on inflammation in a murine model of kidney I/R injury. NAC-pentasaccharide was as effective as fondaparinux at inhibiting the binding of U937 cells to P-selectin.In addition, NAC-pentasaccharide significantly reduced IL-6 and MIP-2 expression and injury in the kidney I/R model.These findings indicate that the anti-inflammatory activity of fondaparinux can be dissociated from its anticoagulant activity and that NACpentasaccharide is protective in kidney I/R injury.

Keywords

Anticoagulant - inflammation - animal model - ischemia-reperfusion injury

Full Text

References

References
1 Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation 2004; 110 (9 Suppl 1) I19-I26.
2 Turpie AG, Eriksson BI, Lassen MR. et al. Fondaparinux, the first selective factor Xa inhibitor. Curr Opin Hematol 2003; 10: 327-32.
3 Herbert JM, Herault JP, Bernat A. et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91: 4197-205.
4 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10.
5 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-11.
6 Ludwig RJ, Alban S, Bistrian R. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo . Thromb Haemost 2006; 95: 535-40.
7 Tyrrell DJ, Horne AP, Holme KR. et al. Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv Pharmacol 1999; 46: 151-208.
8 Wang L, Brown JR, Varki A. et al. Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 2002; 110: 127-36.
9 Koenig A, Norgard-Sumnicht K, Linhardt R. et al. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.J Clin Invest 1998; 101: 877-89.
10 Nelson RM, Cecconi O, Roberts WG. et al. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood 1993; 82: 3253-8.
11 Frank RD, Schabbauer G, Holscher T. et al. The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. J Thromb Haemost 2005; 03: 531-40.
12 Miura M, Fu X, Zhang QW. et al. Neutralization of Gro alpha and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury. Am J Pathol 2001; 159: 2137-45.
13 Weitz JI, Young E, Johnston M. et al. Vasoflux, a new anticoagulant with a novel mechanism of action. Circulation 1999; 99: 682-9.
14 Singbartl K, Green SA, Ley K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure. FASEB J 2000; 14: 48-54.
15 Wei M, Tai G, Gao Y. et al. Modified heparin inhibits P-selectin-mediated cell adhesion of human colon carcinoma cells to immobilized platelets under dynamic flow conditions. J Biol Chem 2004; 279: 29202-10.
16 Gao Y, Li N, Fei R. et al. P-Selectin-mediated acute inflammation can be blocked by chemically modified heparin, RO-heparin. Mol Cells 2005; 19: 350-5.
17 Wei M, Gao Y, Tian M. et al. Selectively desulfated heparin inhibits P-selectin-mediated adhesion of human melanoma cells. Cancer Lett 2005; 229: 123-6.
18 Gao Y, Wei M, Zheng S. et al. Chemically modified heparin inhibits the in vitro adhesion of nonsmall cell lung cancer cells to P-selectin. J Cancer Res Clin Oncol 2006; 132: 257-64.